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ARTICLE IN BRIEF

Two papers strongly discredit the association of the XMRV retrovirus with chronic fatigue syndrome (CFS). One found no evidence of XMRV in blood samples from patients with CFS from a single clinical practice. The second study provides evidence that the XMRV found in the CFS patients in the original study is likely due to laboratory contamination from mouse DNA.

In 2009, when Science published a startling study linking chronic fatigue syndrome (CFS) to an infectious retrovirus called XMRV, reaction was immediate. Patients battling the condition considered it a vindication in the face of skepticism by some in the medical community that CFS exists as a discrete condition, and hoped to see new avenues for treatment. Meanwhile, blood banks banned people diagnosed with CFS from donating out of concern that they might pass along XMRV with their blood.

But neurologists, for the most part, remained skeptical. In a Dec. 3, 2009 article in Neurology Today, several called the results premature and said they were wary of the hype. “It's been one virus after another,” said Thomas D. Sabin, MD, professor of neurology at Tufts Medical Center and co‐editor of the 1993 book Chronic FatigueSyndrome (Lippincott Williams & Wilkins). “Each time, there's been great excitement, and then it's faded. Right now we should await confirmatory evidence from other laboratories.”

Less than two years later, much of that evidence is in, and it appears that neurologists were justified in their caution. A series of attempts to replicate the findings of the original authors — led by Judy Mikovits, PhD, research director of the Whittemore Peterson Institute for Neuro‐Immune Disease, a privately funded institution affiliated with the University of Nevada‐Reno — have proven fruitless. And on June 2, ‐Science published two papers that appear to strongly discredit the XMRV theory of CFS.

NO EVIDENCE OF VIRUS IN BLOOD

In one paper, a team of US researchers led by senior investigator Jay Levy, MD, director of the Laboratory for Tumor and AIDS Virus Research at the University of California–San Francisco, found no evidence of XMRV or other murine‐like gammaretroviruses (MLVs) in blood samples from 61 patients with CFS from a single clinical practice, 43 of whom had previously been identified as XMRV‐positive. (The original paper reported that xenotropic murine XMRV could be detected in 67 percent of 101 patients with CFS, compared to just 3.7 percent of 218 healthy controls.)

They also found that these MLVs were susceptible to inactivation by sera in both patients with CFS and healthy controls — meaning that humans are an unlikely vector for the establishment of a thriving MLV infection.

“These findings are from an eminently experienced and eminently respected group, and simply cannot confirm any of the aspects of the original study,” said Neurology Today Associate Editor Kenneth Tyler, MD, Reuler‐Lewin Family Professor and chair of the department of neurology at the University of Colorado‐Denver, who was not involved with the studies.

The second study provides further evidence for what other researchers have also found since the publication of the original paper: that the XMRV found in the CFS patients in the original study is likely due to laboratory contamination from mouse DNA. A nationwide team, led by Tobias Paprotka, PhD, of the Viral Mutation Section of the HIV Drug Resistance Program at the National Cancer Institute, tracked XMRV to its source: a unique recombination event between two endogenous MLVs that took place around in the mid‐1990s, in a nude mouse carrying a specific xenograft. The authors concluded that the probability that such a recombination event could occur again, by random chance, is remote — so in all likelihood, “any XMRV isolates with the same or nearly the same sequences identified elsewhere originated from this event.”

“There's no way that virus could have existed, in any way that we could understand, in a human population,” Dr. Tyler explained. “It's composed of two endogenous mouse viruses, so such an infection in humans makes no sense. This just adds further weight to the growing conclusion that what they were amplifying was presumably a contamination in their assay. I think that's what most people in the field believe — that one or more of their reagents or specimens, probably reagents given the high positivity rate, were contaminated with mouse material that included DNA from which this XMRV could be amplified.”

WHAT NOW?

So is the matter settled? Many scientists seem to think so. Indeed, the editors of Science took the unusual step of publishing an “Expression of Editorial Concern” from its editor‐in‐chief Bruce Alberts, PhD, about the original study, as well as retroactively attaching a “Science Statement on Editorial Expression of Editorial Concern,” further expanding on comments by Dr. Alberts, to the original paper. The journal indicates that it “will take further action” when ongoing NIH‐sponsored studies of XMRV (led by Columbia University virologist W. Ian Lipkin, MD) are complete.

The original authors stand by their findings, however. Dr. Mikovits declined a request for comment from Neurology Today, but in an interview with Medscape Medical News, she said: “There are no data in Knox et al to support the authors' conclusions or those expressed in the Editorial Expression of Concern. In fact, a close look at western blots shows seropositive patients. They did not use our assays for infectious virus. A glaring example of this is that the infectious viral assay used in Knox et al uses [less sensitive] mink lung cells as a target. Mink lung cells do not support the growth of all animal xeno‐ and polytropic viruses.”

“She would argue that regardless of the original source, this is a virus or family of viruses that is now being passed in humans, and responsible for the illness,” said James Baraniuk, MD, an associate professor of medicine in the Division of Rheumatology, Allergy and Immunology at Georgetown University School of Medicine and a leading researcher on chronic fatigue syndrome, who has spoken with Dr. Mikovits on the issue.

But as exciting as the original hypothesis might have been, Dr. Baraniuk said, he has to disagree. “I think that the weight of the evidence makes this contention a very low probability. Based on these new studies, and the other negative studies that have been published, including the inability to identify the virus in sensitive assays in Europe in laboratories that did not use mouse antibodies, I believe that I would have to go with the conclusion that this is a recombinant mouse virus that contaminated the original samples. The use of murine monoclonal antibodies to identify proteins would be another source for this type of contamination.”

It's understandable that researchers and CFS patients are disheartened by the findings, Dr. Tyler said. “There's a lot of emotional content around this disease, and it's an emotionally invested group of patients. It was an exciting finding because we already had antiretroviral drugs, and the suggestion that there was an active, ongoing viral process meant that ARVs might be efficacious. Now, we're back to where we were before this paper came out.”

Dr. Baraniuk thinks, however, there are lessons to be learned from the data. “The research involved [in studying the proposed XMRV link] has brought new concepts and advanced what we understand about the biology and the pathogenesis of chronic fatigue syndrome, and the scientific community has been very quickly energized to investigate this issue.”

He believes that the cooperative infrastructure around this investigation will bear fruit in further study of CFS as well as other conditions. “If you just focus on the retrovirology, these authors have done a fantastic piece of detective work. It took huge resources to be able to understand the biology of this new entity, XMRV, and to establish that it is very unlikely to be a cause of CFS,” Dr. Baraniuk said. “The cooperation involved and the speed with which they came up with an explanation, I think, is almost unprecedented. I think it's an excellent model of how to investigate a new breakthrough like this.”

And although XMRV may go by the wayside as a candidate virus for CFS, that doesn't mean virology overall is completely dismissed. “All of these studies were very focused, dealing with evidence for or against a very specific viral candidate and not extendable more globally than that,” said Dr. Tyler. “People that know the virus may still come out and say that some of the other data related to cytokines makes the idea of a viral trigger or factor involved in this a plausible hypothesis.”

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